JPH06192097A - Therapeutic agent for infectious disease - Google Patents

Abstract

PURPOSE:To prepare therapeutic agent for infectious diseases, comprising a specific carbostyril derivative (salt) as an active ingredient, having macrobiotic effect on endotoxin shock and high effectiveness against the infectious diseases, especially sepsis causing critical systemic symptoms. CONSTITUTION:This therapeutic agent for infectious diseases is obtained by using a carbostyril derivative of the formula (R is benzoyl which may have a lower alkoxy group on the phenyl ring; the bond between the carbon atoms at the 3-and 4-positions of the carbostyril skeleton denotes single or double bond) {e.g. 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril} and/or its salt as an active ingredient, adding an additive such as an excipient (e.g. starch), a lubricant (e.g. magnesium stearate) and a disintegrating agent (e.g. lactose) thereto and forming the resultant blend into a tablet. This medicine has macrobiotic effect on endotoxin shock and high effectiveness against the infectious diseases, especially sepsis causing critical systemic symptoms.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for infectious diseases containing a specific carbostyril derivative as an active ingredient.

[0002]

2. Description of the Related Art As a therapeutic agent for various bacterial infections, basically, antibiotics and antibacterial agents having an antibacterial spectrum are used for their strains.
A therapeutic agent that can exert a satisfactory effect on, for example, sepsis (Sepsis) as a serious disease directly related to the prognosis of life has not been developed yet.

That is, in the above-mentioned sepsis, pathogenic bacteria from purulent nests as primary nests existing in body tissues or organs continuously or intermittently flow into the blood to form secondary infected foci throughout the body due to blood circulation distribution. It is a systemic infectious disease that causes serious systemic symptoms such as chills, fever and shock due to toxins and metabolites produced by pathogenic bacteria. As the cause,
Recently, MRSA (Methicillin-resistant Straphylococ)
cus aureus; Staphylococcus aureus resistant to penicillinase-resistant penicillin), which is becoming a problem as a pathogen for nosocomial infections.

As a treatment method for the above-mentioned sepsis, based on the administration of antibiotics, water, electrolytes, etc. are generally used as a general therapy, cardiovascular protection, prevention of exacerbation of the primary disease, etc. are attempted, and steroids are used depending on the situation. Careful systemic management such as adjuvant therapy by administration of drugs and immunoglobulins and careful attention to the expression of DIC are performed. In addition, for septic shock, endotoxin shock, etc. associated with the above diseases,
Large doses of antibiotics effective against Gram-negative bacilli have been administered.

On the other hand, recently, as a factor causing shivering, high fever, shock, etc. at the time of bacterial infection, TNF-
Reported overproduction of α (cancer necrosis factor-α),
TNF-as the shock inducer for treating infectious diseases
The use of antibodies against α is being tried. However,
The effect is not very good, and it is difficult to say enough (Pennington, J., ASM News, 58 (9), 479-482 (1992).
].

As described above, the treatment of infectious diseases, especially sepsis requires systemic management corresponding to systemic symptoms.
There are still few therapeutic agents that can cope with serious general conditions such as shock, and therefore, the treatment of such infectious diseases is not always satisfactory.

[0007]

The object of the present invention is to provide a new therapeutic agent showing high efficacy against the above-mentioned infectious diseases, particularly sepsis.

As a result of intensive studies conducted by the present inventors for the purpose described above, the carbostyril derivative represented by the following general formula (1) and a salt thereof, which were previously developed by the present inventors as an active ingredient for cardiotonic agents, The present inventors have completed the present invention by finding the fact that they are effective as therapeutic agents for infectious diseases by a new mechanism of action which meets the above-mentioned object, and in particular that the compounds have a life-prolonging effect on endotoxin shock.

That is, according to the present invention, there is provided an infectious disease therapeutic agent comprising a carbostyril derivative represented by the following general formula (1) and / or a salt thereof as an active ingredient.

[0010]

[Chemical 2]

[In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. The carbon-carbon bond between the 3-position and 4-position of the carbostyril skeleton represents a single bond or a double bond. Further, according to the present invention, the above-mentioned infectious diseases wherein the carbostyril derivative is 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril and / or a salt thereof. Therapeutic agent,
In particular, a therapeutic agent for sepsis is provided.

In the therapeutic agent for infectious diseases of the present invention, the carbostyril derivative represented by the general formula (1) and its salt as an active ingredient and the production method thereof are described in, for example, Japanese Patent Publication No.
No. 43747, and it is also known that the carbostyril derivative is useful as a cardiotonic agent. However, the therapeutic effect on infectious diseases according to the present invention is not related to the cardiotonic action of the above carbostyril derivative, and, of course, cannot be predicted from the cardiotonic action.

More specifically, each group represented by the above general formula (1) is as follows.

That is, as the lower alkoxy group, for example, a linear or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group and the like. Can be illustrated.

The benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring includes, for example, benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl and 3-ethoxybenzoyl. , 4-ethoxybenzoyl, 3-isopropoxybenzoyl, 4-butoxybenzoyl, 2-pentyloxybenzoyl, 3-hexyloxybenzoyl, 3,4-dimethoxybenzoyl,
It may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent on the phenyl ring such as 2,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzoyl groups. A benzoyl group can be illustrated.

The salt of the carbostyril derivative represented by the general formula (1) includes a pharmaceutically acceptable acid addition salt. Specific examples of the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. An organic acid such as an acid can be exemplified.

The carbostyril derivative represented by the general formula (1) and / or its salt, which is the active ingredient of the therapeutic agent for infectious diseases of the present invention, is usually used in the form of a general pharmaceutical preparation. Such a preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.)
Etc. can be illustrated.

In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,
Binders such as potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, moisturizers such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, refined talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet.

In the case of molding in the form of pills, various carriers conventionally known in this field can be widely used, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil,
Examples include excipients such as kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrating agents such as laminaranthantene.

In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into a solution, emulsion and suspension, they are diluted. As the agent, all agents commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose, glycerin or the like for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. are added. You may. If necessary, colorant,
Preservatives, flavors, flavors, sweeteners and other pharmaceuticals may be included in the pharmaceutical preparation.

The amount of the compound of the general formula (1) contained as an active ingredient in the therapeutic agent for infectious diseases of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually about 1 to 7 in the whole composition.
It is suitable that the amount is 0% by weight, preferably about 1 to 30% by weight.

The administration method of the pharmaceutical preparation of the present invention thus obtained is not particularly limited, and it is determined according to various preparation forms, the age and sex of the patient, other conditions, and the degree of disease. For example, a pharmaceutical preparation in the form of an injection may be administered by intravenous, intramuscular, subcutaneous, intracutaneous, intraperitoneal administration, etc., which may be mixed with an ordinary replenishing solution such as glucose or amino acid as necessary. It can also be administered. Tablets, pills, granules,
The pharmaceutical preparation of the present invention in a solid dosage form such as a capsule or a liquid dosage form for oral administration can be administered orally or enterally. Suppositories can also be administered rectally.

The dose of the therapeutic agent for infectious diseases of the present invention can be appropriately selected from a wide range and is not particularly limited, but in general clinical use, the carbostyril derivative of general formula (1) (and its salt) is used. However, the amount is usually selected from the range of about 0.5 to 30 mg per 1 kg of body weight per day, and the active ingredient in the dosage unit form is about 1 to 1 mg.
It is suitable to contain 000 mg. In addition, the administration of the therapeutic agent for infectious disease of the present invention can be divided into once a day or 3 to 4 times a day.

[0025]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a therapeutic agent for infectious diseases, especially a therapeutic agent for sepsis, which comprises a carbostyril derivative represented by the general formula (1) and / or a salt thereof as an active ingredient.
The therapeutic agent for infectious diseases of the present invention has high efficacy and is particularly excellent in terms of prolonging life against endotoxin shock.

[0026]

EXAMPLES In order to explain the present invention in more detail, formulation examples and pharmacological test examples are given below.

[0027]

[Formulation Example 1] 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets were produced.

[0028]

[Formulation Example 2] 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 150 g Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropylmethyl cellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40 g After mixing and polishing the above active ingredient compounds, Avicel, corn starch and magnesium stearate, sugar coating R10 mm
Tablet with the key. The obtained tablets are hydroxypropylmethyl cellulose, polyethylene glycol-600.
A film-coated tablet consisting of 0, castor oil and methanol is coated to produce a film-coated tablet.

[0029]

Formulation Example 3 6- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 150.0 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium lauryl sulfate 3.0 g Dry Magnesium starate 3.0 g Ethanol Appropriate amount The above active ingredient compound, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture was added to No. Sifted with 60 screen, polyvinylpyrrolidone, carbowax 1500
And wet granulation with an alcoholic solution containing Carbowax 6000. Alcohol is added as needed to make the powder into a pekato mass. Add corn starch and continue mixing until uniform particles are formed. No. Pass through 10 screens, place in trays and dry in oven at 100 ° C for 12-14 hours. The dried particles were Sieve through a 16 screen, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compression mold to desired shape in tablet press.

The core is treated with varnish and talc is sprinkled to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied in order to make the tablets completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished to prepare tablets of uniform gloss.

[0032]

[Pharmacological Test Example 1] 6- [4- (3,
4-dimethoxybenzoyl) -1-piperazinyl]-
The following pharmacological tests were carried out using 3,4-dihydrocarbostyril (hereinafter referred to as "Compound 1").

That is, a male BALB / c mouse (Japan SL
(Purchased from Company C) was divided into 3 groups (10 mice per group), and 50 mg / kg and 500 mg / kg of Compound 1 were orally administered to each mouse of the first group and the second group. As a control, the third group contained 0.5% carboxymethyl cellulose (C
MC, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) was orally administered.

One hour after each administration, 20 mg of D-galactosamine (manufactured by Wako Pure Chemical Industries) was intraperitoneally administered to each group of mice, and immediately 10 μg / mouse of LPS (Escherichia coli 055: B5 derived, manufactured by Sigma) was intravenously administered. When administered internally, endotoxin shock was induced.

From the LPS administration to the 7th day, the life and death of the test animals in each group were observed.

The results are shown in FIG.

In the figure, the results of statistical treatment performed on the third group (control, solvent-administered group) by the Wilcockson method (Generailzed Wilcoxon) are shown as p <0.01 and p <0. Shown as .05.

From FIG. 1, in comparison with the third group (control, solvent administration group), in the compound 1 administration group (first group and second group),
A significant life prolonging effect was observed depending on the concentration of Compound 1 administered. From this, it was revealed that Compound 1 can exert a life-prolonging effect on endotoxin shock, and based on this, it is useful as a therapeutic agent for infectious diseases.

[Brief description of drawings]

FIG. 1 is a graph showing the results of a life-prolonging effect test for endotoxin shock described in Pharmacological Test Example 1 of the present invention.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shoichi Adachi 9349-3, Ishihara-cho, Takasaki-shi Gunma 9 (72) Inventor Hiroyuki Ichikawa 3-11 Nakadori-cho, Tokushima-shi, Tokushima (72) Inventor Seiji Akamatsu 223-1 Kawasaki, Omamachi, Naruto City, Tokushima Prefecture (72) Inventor Shiro Saito 2294-80 Yamanamachi, Takasaki City, Gunma Prefecture

Claims (2)

[Claims] 1. A general formula: [In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. Carbostyryl skeleton 3
The carbon-carbon bond between the 4-position and the 4-position represents a single bond or a double bond. ] A therapeutic agent for an infectious disease, which comprises a carbostyril derivative represented by the following formula and / or a salt thereof as an active ingredient. 2. The carbostyril derivative is 6- [4-
(3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl.
The therapeutic agent for infectious disease according to 1.